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Smallpox is an infectious disease unique to humans,
caused by either of two virus
variants, Variola major and Variola minor. The
disease is also known by the Latin names
Variola or Variola vera, which is a derivative of
the Latin varius, meaning spotted, or varus,
meaning "pimple". The term "smallpox" was first used in Europe in
the 15th century to distinguish variola from the "great pox"
(syphilis).

Smallpox localizes in small blood
vessels of the skin and in the mouth and throat. In the skin,
this results in a characteristic maculopapular rash, and later, raised
fluid-filled blisters. V. major
produces a more serious disease and has an overall mortality rate of 30–35%. V. minor
causes a milder form of disease (also known as alastrim, cottonpox, milkpox, whitepox, and Cuban
itch) which kills about 1% of its victims. Long-term complications
of V. major infection include characteristic scars,
commonly on the face, which occur in 65–85% of survivors. Blindness resulting from corneal ulceration and scarring, and limb
deformities due to arthritis and osteomyelitis are less common complications,
seen in about 2–5% of cases.

Smallpox is believed to have emerged in human populations about 10,000 BC. The
disease killed an estimated 400,000 Europeans each year during the
18th century (including five monarchs), and
was responsible for a third of all blindness. Of all those
infected, 20–60%—and over 80% of infected children—died from the
disease.

During the 20th century, it is estimated that smallpox was
responsible for 300–500 million deaths. In the early 1950s an
estimated 50 million cases of smallpox occurred in the world each
year. As recently as 1967, the World Health Organization (WHO)
estimated that 15 million people contracted the disease and that
two million died in that year. After successful vaccination campaigns throughout the 19th and
20th centuries, the WHO certified the eradication of smallpox in
December 1979. To this day, smallpox is the only human infectious
disease to have been completely eradicated.

Cause

Smallpox is caused by infection with variola virus, which belongs
to the genus Orthopoxvirus, the family
Poxviridae, and subfamily
chordopoxvirinae. Variola is a large brick-shaped virus measuring
approximately 302 to 350 nanometers by 244
to 270 nm, with a single linear double
stranded DNAgenome 186 kilobase pairs (kbp) in size and containing a
hairpin loop at each end. The two
classic varieties of smallpox are variola major and variola minor.
The closest viral relative is molluscum contagiosum, which, like
smallpox, infects only humans. However, unlike variola species,
molluscum infection is benign.

Four orthopoxviruses cause infection in humans: variola, vaccinia, cowpox, and
monkeypox. Variola virus infects only
humans in nature, although primates and other animals have been
infected in a laboratory setting. Vaccinia, cowpox, and monkeypox
viruses can infect both humans and other animals in nature.

The lifecycle of poxviruses is complicated by having multiple
infectious forms, with differing mechanisms of cell entry.
Poxviruses are unique among DNA viruses in that they replicate in
the cytoplasm of the cell rather than in
the nucleus. In order to replicate,
poxviruses produce a variety of specialized proteins not produced
by other DNA viruses, the most important
of which is a viral-associated DNA-dependent RNA
polymerase.Both enveloped and
unenveloped virions are infectious. The viral envelope is made of
modified Golgi membranes containing
viral-specific polypeptides, including hemagglutinin. Infection with either variola
major or variola minor confers immunity against the other.

Evolution

Smallpox appears to have evolved from an African rodent-borne
variola-like virus. The date of this evolution is uncertain at
present and estimates vary between 16,000 and 68,000 years ago. The
more severe form (variola major) originated in Asia between 400 and
1600 years ago. A second form –alastrim minor– found in West Africa and the Americas is thought to have
evolved between 1,400 and 6,300 years ago. This clade gave rise to two subclades that diverged at
least 800 years ago.

Transmission

Transmission of smallpox occurs through inhalation of airborne
variola virus, usually droplets expressed from the oral, nasal, or
pharyngealmucosa of
an infected person. It is transmitted from one person to another
primarily through prolonged face-to-face contact with an infected
person, usually within a distance of 6 feet, but can also be spread
through direct contact with infected bodily
fluids or contaminated objects (fomites)
such as bedding or clothing. Rarely, smallpox has been spread by
virus carried in the air in enclosed settings such as buildings,
buses, and trains. The virus can cross the placenta, but the incidence of congenital smallpox is relatively low.Smallpox is
not notably infectious in the prodromal
period and viral shedding is usually delayed until the appearance
of the rash, which is often accompanied by lesions in the mouth and pharynx. The virus can be
transmitted throughout the course of the illness, but is most
frequent during the first week of the rash, when most of the skin
lesions are intact. Infectivity wanes in 7 to 10 days when scabs
form over the lesions, but the infected person is contagious until
the last smallpox scab falls off.

Smallpox is highly contagious, but generally spreads more slowly
and less widely than some other viral diseases, perhaps because
transmission requires close contact and occurs after the onset of
the rash. The overall rate of infection is also affected by the
short duration of the infectious stage. In temperate areas, the number of smallpox infections
were highest during the winter and spring. In tropical areas,
seasonal variation was less evident and the disease was present
throughout the year. Age distribution of smallpox infections
depends on acquired immunity.
Vaccinationimmunity declines over time and is
probably lost in all but the most recently vaccinated populations.
Smallpox is not known to be transmitted by insects or animals and
there is no asymptomatic
carrier state.

Signs and symptoms

There are two clinical forms of smallpox. Variola major is the
severe and most common form of smallpox, with a more extensive rash
and higher fever. There are four types of variola major smallpox
based on the Rao classification: ordinary, modified, flat, and
hemorrhagic. Historically, variola major has an overall fatality rate of about 30%; however, flat and
hemorrhagic smallpox are usually fatal. In addition, a form called
variola sine eruptione (smallpox without rash) is seen
generally in vaccinated persons. This form is marked by a fever
that occurs after the usual incubation period and can be confirmed
only by antibody studies or, rarely, by virus isolation.

Variola minor is a less common presentation of smallpox, and a much
less severe disease, with historical death rates of 1% or less.
Subclinical (asymptomatic) infections
with variola virus have also been noted, but are not believed to be
common.

Child showing rash due to
ordinary-type smallpox (variola major)

The incubation period between
contraction and the first obvious symptoms of the disease is around
12 days. Once inhaled, variola virus invades the oropharyngeal
(mouth and throat) or the respiratory
mucosa, migrates to regional lymph
nodes, and begins to multiply. In the initial growth phase the
virus seems to move from cell to cell, but around the 12th day,
lysis of many infected cells occurs and the
virus is found in the bloodstream in large
numbers (this is called viremia),
and a second wave of multiplication occurs in the spleen, bone marrow, and lymph nodes. The initial or
prodromal symptoms are similar to other viral diseases such as
influenza and the common cold: fever (at
least ), muscle pain, malaise, headache,
prostration, and as the digestive tract is commonly involved,
nausea and vomiting and backache often occur. The prodrome, or
preeruptive stage, usually lasts 2–4 days. By days 12–15 the first
visible lesions—small reddish spots called enanthem—appear
on mucous membranes of the mouth, tongue, palate, and throat, and temperature falls to near
normal. These lesions rapidly enlarge and rupture, releasing large
amounts of virus into the saliva.

Smallpox virus preferentially attacks skin cells, causing the
characteristic pimples (called macules)
associated with the disease. A rash develops on the skin 24 to 48
hours after lesions on the mucous membranes appear. Typically the
macules first appear on the forehead, then rapidly spread to the
whole face, proximal portions of extremities, the trunk, and lastly
to distal portions of extremities. The process takes no more than
24 to 36 hours, after which no new lesions appear. At this point
Variola major infection can take several very different
courses.

Ordinary

Ninety percent or more of smallpox cases among unvaccinated persons
are of the ordinary type. In this form of the disease, by the
second day of the rash, the macules become raised papules.
By the third or fourth day the papules fill with an opalescent
fluid to become vesicles. This fluid becomes
opaque and turbid within 24–48 hours, giving them the appearance
of pustules; however, the so-called pustules
are filled with tissue debris, not pus.

By the sixth or seventh day, all the skin lesions have become
pustules. Between 7 and 10 days the pustules mature and reach their
maximum size. The pustules are sharply raised, typically round,
tense, and firm to the touch. The pustules are deeply embedded in
the dermis, giving them the feel of a small bead in the skin. Fluid
slowly leaks from the pustules, and by the end of the second week
the pustules deflate, and start to dry up, forming crusts (or
scabs). By day 16-20 scabs have formed over all the lesions, which
have started to flake off, leaving de-pigmented scars.

Ordinary smallpox generally produces a discrete rash, in
which the pustules stand out on the skin separately. The
distribution of the rash is densest on the face; denser on the
extremities than on the trunk; and on the extremities, denser on
the distal parts than on the proximal. The palms of the hands and
soles of the feet are involved in the majority of cases. In some
cases, the blisters merge together into sheets, forming a
confluent rash, which begin to detach the outer layers of
skin from the underlying flesh. Patients with confluent smallpox
often remain ill even after scabs have formed over all the lesions.
In one case series, the case-fatality rate in confluent smallpox
was 62%.

Modified

Referring to the character of the eruption and the rapidity of its
development, modified smallpox occurs mostly in previously
vaccinated people. In this form the prodromal illness still occurs
but may be less severe than in the ordinary type. There is usually
no fever during evolution of the rash. The skin lesions tend to be
fewer and evolve more quickly, are more superficial, and may not
show the uniform characteristic of more typical smallpox. Modified
smallpox is rarely, if ever, fatal. This form of variola major is
more easily confused with chickenpox.

This man is suffering from severe
hemorrhagic-type smallpox.

Malignant

In Malignant-type smallpox (also called flat smallpox) the lesions
remain almost flush with the skin at the time when raised vesicles
form in ordinary-type smallpox. It is unknown why some people
develop this type of disease. Historically, malignant smallpox
accounted for 5%–10% of cases, and the majority (72%) were in
children. Malignant smallpox is accompanied by a severe prodromal phase that lasts 3–4 days, prolonged
high fever, and severe symptoms of toxemia.
The rash on the tongue and palate is usually extensive. The skin
lesions mature very slowly and by the seventh or eighth day the
lesions are flat and appear to be buried in the skin. Unlike
ordinary-type smallpox, the vesicles contain very little fluid, are
soft and velvety to the touch, and may contain hemorrhages.
Malignant smallpox is nearly always fatal.

Hemorrhagic

Hemorrhagic smallpox is a severe form of
smallpox that is accompanied by extensive bleeding into the skin,
mucous membranes, and gastrointestinal tract. This form developed
in perhaps 2% of infections and occurred mostly in adults. In
hemorrhagic smallpox the skin does not blister, but remains smooth.
Instead, bleeding occurs under the skin, making the skin look
charred and black, hence this form of the disease is also known as
black pox.

In the early, or fulminating form, hemorrhaging appears on the
second or third day as sub-conjunctival
bleeding turns the whites of the eyes deep red. Hemorrhagic
smallpox also produces a dusky erythema,
petechiae, and hemorrhages in the spleen,
kidney, serosa, muscle, and, rarely, the
epicardium, liver,
testes, ovaries and
bladder. Death often occurs suddenly between
the fifth and seventh days of illness, when only a few
insignificant skin lesions are present. A later form of the disease
occurs in patients who survive for 8–10 days. The hemorrhages
appear in the early eruptive period, and the rash is flat and does
not progress beyond the vesicular stage. Patients in the early
stage of disease show a decrease in coagulation factors (e.g. platelets, prothrombin,
and globulin) and an increase in
circulating antithrombin. Patients in
the late stage have significant thrombocytopenia; however, deficiency of
coagulation factors is less severe. Some in the late stage also
show increased antithrombin. This form of smallpox occurs in
anywhere from 3–25% of fatal cases depending on the virulence of
the smallpox strain. Hemorrhagic smallpox is usually fatal.

Diagnosis

Smallpox virus pocks on the
chorioallantoic membrane of a developing chick.

The clinical definition of smallpox is an illness with acute onset
of fever greater than 101°F (38.3°C) followed by a rash
characterized by firm, deep seated vesicles or pustules in the same
stage of development without other apparent cause. If a clinical
case is observed, smallpox is confirmed using laboratory
tests.

Microscopically, poxviruses produce
characteristic cytoplasmic inclusions,
the most important of which are known as Guarnieri bodies, and are the sites of
viral replication. Guarnieri
bodies are readily identified in skin biopsies stained with
hematoxylin and eosin, and appear as pink blobs. They are found in
virtually all poxvirus infections but the absence of Guarnieri
bodies cannot be used to rule out smallpox. The diagnosis of an
orthopoxvirus infection can also be made rapidly by electron microscopic examination of
pustular fluid or scabs. However, all orthopoxviruses exhibit
identical brick-shaped virions by electron microscopy.

Chickenpox was commonly confused with
smallpox in the immediate post-eradication era. Chickenpox and
smallpox can be distinguished by several methods. Unlike smallpox,
chickenpox does not usually affect the palms and soles.
Additionally, chickenpox pustules are of varying size due to
variations in the timing of pustule eruption: smallpox pustules are
all very nearly the same size since the viral effect progresses
more uniformly. A variety of laboratory methods are available for
detecting chickenpox in evaluation of suspected smallpox
cases.

Prognosis

The overall case-fatality rate for ordinary-type smallpox is about
30%, but varies by pock distribution: ordinary type-confluent is
fatal about 50–75% of the time, ordinary-type semi-confluent about
25–50% of the time, in cases where the rash is discrete the
case-fatality rate is less than 10%. The overall fatality rate for
children younger than 1 year of age is 40%–50%. Hemorrhagic and
flat types have the highest fatality rates. The fatality rate for
flat-type is 90% or greater and nearly 100% is observed in cases of
hemorrhagic smallpox. The case-fatality rate for variola minor is
1% or less. There is no evidence of chronic or recurrent infection
with variola virus.

In fatal cases of ordinary smallpox, death usually occurs between
the tenth and sixteenth days of the illness. The cause of death
from smallpox is not clear, but the infection is now known to
involve multiple organs. Circulating immune complexes, overwhelming viremia, or an uncontrolled immune response may be contributing factors.
In early hemorrhagic smallpox, death occurs suddenly about six days
after the fever develops. Cause of death in hemorrhagic cases
involved heart failure, sometimes
accompanied by pulmonary edema. In
late hemorrhagic cases, high and sustained viremia, severe platelet loss and poor immune response were often
cited as causes of death. In flat smallpox modes of death are
similar to those in burns, with loss of fluid, protein and electrolytes beyond the capacity of the body to
replace or acquire, and fulminating sepsis.

Complications

Complications of smallpox arise most commonly in the respiratory system and range from simple
bronchitis to fatal pneumonia. Respiratorycomplications tend to
develop on about the eighth day of the illness and can be either
viral or bacterial in origin. Secondary bacterial infection of the skin is a relatively
uncommon complication of smallpox. When this occurs, the fever
usually remains elevated.

Other complications include encephalitis (1 in 500 patients), which is more
common in adults and may cause temporary disability; permanent
pitted scars, most notably on the face; and complications involving
the eyes (2% of all cases). Pustules can form on the eyelid,
conjunctiva, and cornea, leading to complications such as conjunctivitis, keratitis, corneal
ulcer, iritis, iridocyclitis, and optic atrophy. Blindness results
in approximately 35% to 40% of eyes affected with keratitis and
corneal ulcer. Hemorrhagic smallpox can cause subconjunctival and
retinal hemorrhages. In 2% to 5% of young
children with smallpox, virions reach the joints and bone, causing
osteomyelitis variolosa.
Lesions are symmetrical, most common in the elbows, tibia, and fibula, and
characteristically cause separation of an epiphysis and marked periosteal reactions. Swollen joints limit
movement, and arthritis may lead to limb
deformities, ankylosis, malformed bones,
flail joints, and stubby fingers.

Treatment

Smallpox vaccination within three days of exposure will prevent or
significantly lessen the severity of smallpox symptoms in the vast
majority of people. Vaccination four to seven days after exposure
likely offers some protection from disease or may modify the
severity of disease. Other than vaccination, treatment of smallpox
is primarily supportive, such as wound care and infection control,
fluid therapy, and possible ventilator
assistance. Flat and hemorrhagic types of smallpox are treated with
the same therapies used to treat shock, such as fluid resuscitation. Patients with
semi-confluent and confluent types of smallpox may have therapeutic
issues similar to patients with extensive skin burns.

No drug is currently approved for the treatment of smallpox.
However, antiviral treatments have
improved since the last large smallpox epidemics, and studies
suggest that the antiviral drug cidofovir
might be useful as a therapeutic agent. The drug must be
administered intravenously, however,
and may cause serious renal toxicity.

Prevention

The earliest procedure used to prevent smallpox was inoculation (also known as variolation).
Inoculation was allegedly first practiced in
India as early as 1000 BC, and involved either nasal
insufflation of powdered
smallpox scabs, or scratching material from a smallpox lesion into
the skin. However, this idea has been challenged as few of
the ancient Sanskrit medical texts of India
described the process of inoculation. Accounts of
inoculation against smallpox in China can be found
as early as the late 10th century, and the procedure was widely
practiced by the 16th century, during the Ming Dynasty. If successful, inoculation produced lasting
immunity to smallpox. However,
because the person was infected with variola virus, a severe
infection could result, and the person could transmit smallpox to
others. Variolation had a 0.5–2% mortality rate; considerably less
than the 20–30% mortality rate of the disease itself.

In 1796
Edward Jenner, a doctor in Berkeley, Gloucestershire, rural England, discovered
that immunity to smallpox could be produced by inoculating a person
with material from a cowpox lesion.
Cowpox is a poxvirus in the same family as variola. Jenner called
the material used for inoculation vaccine,
from the root wordvacca, which is Latin for cow. The
procedure was much safer than variolation, and did not involve a
risk of smallpox transmission. Vaccination to prevent smallpox was
soon practiced all over the world. During the 19th century, the
cowpox virus used for smallpox vaccination was replaced by vaccinia virus. Vaccinia is in the same
family as cowpox and variola but is genetic
distinct from both. The origin of vaccinia virus and how it came to
be in the vaccine are not known.

The current formulation of smallpox vaccine is a live virus
preparation of infectious vaccinia virus. The vaccine is given
using a bifurcated (two-pronged) needle
that is dipped into the vaccine solution. The needle is used to
prick the skin (usually the upper arm) a number of times in a few
seconds. If successful, a red and itchy bump develops at the
vaccine site in three or four days. In the first week, the bump
becomes a large blister (called a “Jennerian vesicle”) which fills
with pus, and begins to drain. During the second week, the blister
begins to dry up and a scab forms. The scab falls off in the third
week, leaving a small scar.

The antibodies induced by vaccinia
vaccine are cross-protective for other orthopoxviruses (such as
monkeypox, cowpox, and variola (smallpox) viruses). Neutralizing
antibodies are detectable 10 days after first-time vaccination, and
seven days after revaccination. Historically, the vaccine has been
effective in preventing smallpox infection in 95% of those
vaccinated. Smallpox vaccination provides a high level of immunity
for three to five years and decreasing immunity thereafter. If a
person is vaccinated again later, immunity lasts even longer.
Studies of smallpox cases in Europe in the 1950s and 1960s
demonstrated that the fatality rate among persons vaccinated less
than 10 years before exposure was 1.3%; it was 7% among those
vaccinated 11 to 20 years prior, and 11% among those vaccinated 20
or more years prior to infection. By contrast, 52% of unvaccinated
persons died.

There are side effects and risks associated with the smallpox
vaccine. In the past, about 1,000 people for every 1 million people
vaccinated for the first time experienced serious, but
non-life-threatening, reactions including toxic or allergic reaction at the site of the
vaccination (erythema
multiforme), spread of the vaccinia virus to other parts of the
body, and to other individuals. Potentially life-threatening
reactions occurred in 14 to 500 people out of every 1 million
people vaccinated for the first time. Based on past experience, it
is estimated that 1 or 2 people in 1 million (0.000198%) who
receive the vaccine may die as a result, most often the result of
postvaccinial encephalitis or severe
necrosis in the area of vaccination (called
progressive vaccinia).

Given
these risks, as smallpox became effectively eradicated and the
number of naturally-occurring cases fell below the number of
vaccine-induced illnesses and deaths, routine childhood vaccination
was discontinued in the United States in 1972. Routine vaccination of healthcare
workers was discontinued in 1976, and among military recruits in
1990. Military members deploying to the Middle East and Korea still
receive the vaccination. It is now primarily recommended for
laboratory workers at risk for occupational exposure. Mass smallpox
vaccination was abandoned in most European
countries in the early 1970s as well.

Eradication

Since Jenner demonstrated the effectiveness of cowpox to protect
humans from smallpox in 1796, various attempts were made to
eliminate smallpox on a regional scale. As early as 1803, the
Spanish Crown organized a mission (the Balmis expedition) to transport the
vaccine to the Spanish colonies in
the Americas and the Philippines, and establish mass vaccination
programs there.By about 1817, a very solid state vaccination
programme existed in the Dutch East Indies. In British
India a program was launched to propagate smallpox vaccination,
through Indian vaccinators, under the supervision of European
officials. By 1832, the federal government of the
United
States established a smallpox vaccination program for
Native Americans. In 1842, the United Kingdom banned
inoculation, later progressing to mandatory vaccination. The British
government introduced compulsory smallpox vaccination by an Act of
Parliament in 1853. In the United States, from 1843 to 1855 first Massachusetts, and then
other states required smallpox vaccination. Although some
disliked these measures, coordinated efforts against smallpox went
on, and the disease continued to diminish in the wealthy countries.
By 1897, smallpox had largely been eliminated from the United
States. In Northern Europe a number of countries had eliminated
smallpox by 1900, and by 1914, the incidence in most industrialized
countries had decreased to comparatively low levels. Vaccination
continued in industrialized countries, until the mid to late 1970s
as protection against reintroduction. Australia and New Zealand are two notable exceptions; neither experienced
endemic smallpox and never vaccinated widely, relying instead on
protection by distance and strict quarantines.

The first hemisphere-wide effort to
eradicate smallpox was made in 1950 by the Pan American Health
Organization. The campaign was successful in eliminating
smallpox from all American countries except Argentina, Brazil,
Colombia, and Ecuador. In 1958 Professor Viktor Zhdanov, Deputy
Minister of Health for the USSR, called on
the World Health Assembly to undertake a global initiative to
eradicate
smallpox. The proposal (Resolution WHA11.54) was accepted in
1959. At this point, 2 million people were dying every year.
Overall, however, progress towards eradication was disappointing,
especially in Africa and in the Indian subcontinent. In 1967, the World
Health Organization intensified the global smallpox eradication by
contributing $2.4 million annually to the effort. An international
team, the Smallpox Eradication unit, was formed under the
leadership of an American, Donald
Henderson.

To eradicate smallpox, each outbreak had to be stopped from
spreading, by isolation of cases and vaccination of everyone who
lived close by. This process is known as "ring vaccination". The
key to this strategy was monitoring of cases in a community (known
as surveillance) and containment. The initial problem the WHO team
faced was inadequate reporting of smallpox cases, as many cases did
not come to the attention of the authorities. The fact that humans
are the only reservoir for smallpox infection, and that carriers did not exist, played a
significant role in the eradication of smallpox. The WHO
established a network of consultants who assisted countries in
setting up surveillance and containment activities. Early on
donations of vaccine were provided primarily by the Soviet Union
and the United States, but by 1973, more than 80% of all vaccine
was produced in developing countries.

The last
major European outbreak of smallpox was in 1972 in Yugoslavia,
after a pilgrim from Kosovo returned
from the Middle East, where he had
contracted the virus. The epidemic infected 175 people,
causing 35 deaths. Authorities declared martial law, enforced quarantine, and undertook
widespread re-vaccination of the population, enlisting the help of
the WHO. In two months, the outbreak was over. Prior to this, there
had been a smallpox outbreak in May–July 1963 in Stockholm, Sweden, brought
from the Far East by a Swedish sailor; this
had been dealt with by quarantine measures and vaccination of the
local population.

By the end of 1975, smallpox persisted only in the Horn of Africa. Conditions were very
difficult in Ethiopia and Somalia, where there were few roads.
Civil war, famine, and refugees made the task even more difficult.
An intensive surveillance and containment and vaccination program
was undertaken in early and mid-1977. The last naturally
occurring case of indigenous smallpox (Variola minor) was
diagnosed in Ali Maow Maalin, a
hospital cook in Merca, Somalia, on 26 October 1977.The last naturally
occurring case of the more deadly Variola major had been
detected in October 1975 in a two-year-old Bangladeshi girl, Rahima
Banu.

The global eradication of smallpox was certified, based on intense
verification activities in countries, by a commission of eminent
scientists on 9 December 1979 and subsequently endorsed by the
World Health Assembly on 8 May 1980 as Resolution WHA33.3. The
first two sentences of the resolution read: "Having considered the
development and results of the global program on smallpox
eradication initiated by WHO in 1958 and intensified since 1967 …
Declares solemnly that the world and its peoples have won freedom
from smallpox, which was a most devastating disease sweeping in
epidemic form through many countries since earliest time, leaving
death, blindness and disfigurement in its wake and which only a
decade ago was rampant in Africa, Asia and South America."

Post-eradication

The last
cases of smallpox in the world occurred in an outbreak of two cases
(one of which was fatal) in Birmingham, England in 1978.A medical
photographer, Janet Parker, contracted
the disease at the University of Birmingham Medical
School and died on 11 September 1978, after which the
scientist responsible for smallpox research at the university,
Professor Henry Bedson, committed suicide.In light of this accident, all known stocks
of smallpox were destroyed or transferred to one of two WHO
reference laboratories; the Centers for Disease
Control and Prevention (CDC) in the United States and the
State Research Center of Virology and
Biotechnology VECTOR in Koltsovo, Russia. In 1986, the World Health Organization
recommended destruction of the virus, and later set the date of
destruction to be 30 December 1993. This was postponed to 30 June
1995. In 2002 the policy of the WHO changed to be against its final
destruction. Destroying existing stocks would reduce the risk
involved with ongoing smallpox research; the stocks are not needed
to respond to a smallpox outbreak. However, the stocks may be
useful in developing new vaccines, antiviral drugs, and diagnostic
tests.

Biological warfare

The British considered using smallpox as a biological warfare agent during the
French and Indian Wars
(1754–63), against France and its Native American allies at
the Siege of Fort
Pitt. On one occasion in June 1763, two blankets and a
handkerchief that had been exposed to smallpox were given to
representatives of the besieging Delawares with the aim of
spreading the disease and ending the siege. Historians do not agree
on whether this effort to broadcast the disease was successful. It
has also been alleged that smallpox was used as a weapon during the
American Revolutionary
War (1775–83).

During
World War II, scientists from the
United
Kingdom, United
States and Japan were
involved in research into producing a biological weapon from
smallpox. Plans of large scale production were never carried
through as they considered that the weapon would not be very
effective due to the wide-scale availability of a vaccine.

In 1947
the Soviet
Union established a smallpox weapons factory in the city
of Zagorsk, 75 km to the northeast of Moscow.. An
outbreak of weaponized smallpox possibly occurred during testing at
the factory in the 1970s. General Prof. Peter Burgasov, former
Chief Sanitary Physician of the Soviet
Army, and a senior researcher within the Soviet program of
biological weapons described the incident:

“On
Vozrozhdeniya Island in the Aral
Sea, the strongest recipes of smallpox were
tested.Suddenly I was informed that there were
mysterious cases of mortalities in Aralsk. A
research ship of the Aral fleet came to within 15 km of the island
(it was forbidden to come any closer than 40 km). The lab
technician of this ship took samples of plankton twice a day from
the top deck. The smallpox formulation—400 gr. of which was
exploded on the island—”got her” and she became infected. After
returning home to Aralsk, she infected several people including
children. All of them died. I suspected the reason for this and called
the Chief of General Staff of Ministry of Defense and requested to
forbid the stop of the Alma-Ata—Moscow train in
Aralsk. As a result, the epidemic around the country was
prevented. I called Andropov, who at
that time was Chief of KGB, and informed him of the exclusive
recipe of smallpox obtained on Vozrazhdenie Island.”

Others contend that the first patient may have contracted the
disease while visiting Uyaly or Komsomolsk, two cities where the boat
docked.

Responding to international pressures, in 1991 the Soviet
government allowed a joint US-British inspection team to tour four
of its main weapons facilities at Biopreparat. The inspectors were met with
evasion and denials from the Soviet scientists, and were eventually
ordered out of the facility. In 1992 Soviet defector Ken Alibek confirmed that the Soviet bioweapons
program at Zagorsk had produced a large stockpile—as much as twenty
tons—of weaponized smallpox (possibly engineered to resist
vaccines), along with refrigerated warheads
to deliver it. It is not known whether these stockpiles still exist
in Russia. In 1997, however, the Russian government announced that
all of its remaining smallpox samples would be moved to the Vector
Institute in Koltsovo. With the breakup of
the Soviet Union and unemployment of many of the weapons program's
scientists, there is concern that smallpox and the expertise to
weaponize it may have become available to other governments or
terrorist groups who might wish to use virus as means of biological
warfare.

History

Smallpox likely diverged from an ancestral African rodent-borne
variola-like virus between 16,000 and 68,000 years ago. The precise
origins of smallpox are unknown, and most early references to it
are unreliable. Historical records from Asia describe evidence of
smallpox-like disease in medical writings from ancient China (1122
B.C.) and India (as early as 1500 B.C.) Originally published as
Princes and Peasants: Smallpox in History (1983), ISBN
0-226-35177-7 The earliest credible clinical evidence of smallpox
is found in the Egyptianmummies of persons who died some 3000 years ago. It
has been speculated that Egyptian traders brought smallpox to India
during the 1st millennium BC, where it remained as an endemic human
disease for at least 2000 years. Unmistakable descriptions of
smallpox first appeared in the 4th century AD in China and the 7th
century in India. Smallpox was likely introduced in China during
the 1st century AD from the southwest, and in the 6th century was
carried from China to Japan.

The arrival of smallpox in Europe and south-western Asia is less
clear. Smallpox is not described in either the Old or New
Testaments of the Bible, or in literature of the Greeks and
Romans. Scholars agree it is very unlikely such a serious disease
as variola major would have escaped a description by Hippocrates if it existed in the Mediterranean
region. While the Antonine Plague
that swept through the Roman Empire in
165–180 AD may have been caused by smallpox, other historians
speculate that Arab armies first carried
smallpox out of Africa to Southwestern Europe during the 7th and
8th centuries AD. In the 9th century the Persian physician, Rhazes, provided one of the
most definitive observations of smallpox and was the first to
differentiate smallpox from measles and
chickenpox in his Kitab fi al-jadari
wa-al-hasbah (The Book of Smallpox and Measles).
During the Middle Ages, smallpox made
periodic incursions into Europe but did not become established
there until the population increased and population movement became
more active during the time of the Crusades. By the 16th century smallpox was well
established over most of Europe. With its introduction in populated
areas in India, China and Europe, smallpox affected mainly
children, with periodic epidemics that killed up to 30% of those
infected. The appearance of smallpox in Europe is of particular
importance, as successive waves of European exploration and
colonization served to spread the disease to other parts of the
world. By the 16th century it had become an important cause of
morbidity and mortality in the known world.

Smallpox sufferer: Illinois,
1912

There are no credible descriptions of smallpox-like disease in the
Americas before the westward exploration in
the 15th century AD. In 1507 smallpox was introduced into the
Caribbean island of Hispaniola and to the mainland in 1520, when Spanish settlers
from Hispaniola arriving in Mexico brought smallpox with
them. Smallpox devastated the native Amerindian population and was an important factor
in the conquest of the Aztecs and the Incas by the Spaniards. Settlement of the east coast of North
America in 1633 in Plymouth, Massachusetts was also accompanied by devastating outbreaks of
smallpox among Native American populations, and subsequently among
the native-born colonists. Smallpox was introduced into
Australia in 1789 and again in 1829 and
caused devastation among the aborigine, but quickly died out on
both occasions.

By the mid-18th century smallpox was a major endemic disease everywhere in the
world except in Australia and in several small islands. In Europe
smallpox was a leading cause of death in the 18th century, killing
an estimated 400,000 Europeans each year, including five reigning
European monarchs. In Russia every 7th
child born died from smallpox. The widespread use of
variolation in a few countries, notably
Great Britain its North American colonies, and China, somewhat
reduced the impact of smallpox among the wealthy classes during the
latter part of the 18th century, but a real reduction in its
incidence did not occur until vaccination became a common practice
toward the end of the 19th century. Improved vaccines and the
practice of re-vaccination led to a substantial reduction in cases
in Europe and North America, but smallpox remained almost unchecked
everywhere else in the world. In the United States and South Africa
a much milder form of smallpox, variola minor, was
recognized just before the close of the 19th century. By the
mid-20th century variola minor occurred along with
variola major, in varying proportions, in many parts of
Africa. Patients with variola minor experience only a mild
systemic illness, are often ambulant throughout
the course of the disease, and are therefore able to more easily
spread disease. Infection with v. minor induces immunity
against the more deadly variola major form. Thus as v.
minor spread all over the USA, into Canada, the South American
countries and Great Britain it became the dominant form of
smallpox, further reducing mortality rates.

Prominent families throughout the world often had several people
infected by and/or perish from the disease. For example, several
relatives of Henry VIII
survived the disease but were scarred by it. These include his
sister Margaret, Queen of Scotland,
his fourth wife, Anne of Cleves, and
his two daughters: Mary I of
England in 1527 and Elizabeth
I of England in 1562 (as an adult she would often try to
disguise the pockmarks with heavy makeup). His great-niece,
Mary, Queen of Scots,
contracted the disease as a child but had no visible
scarring.

In Europe, deaths from smallpox often changed dynastic succession.
The only surviving son of Henry VIII,
Edward VI, likely died from
complications shortly after apparently recovering from the disease,
thereby rendering his sire's infamous efforts to provide England
with a male heir moot. (His immediate successors were all females.)
Louis XV of France succeeded his
great-grandfather Louis XIV through a
series of deaths of smallpox or measles among those earlier in the
succession line. He himself died of the disease in 1774. William III lost his mother to the
disease when he was only ten years old in 1660, and named his uncle
Charles as legal guardian: her death from smallpox would indirectly
spark a chain of events that would eventually lead to the permanent
ousting of the Stuart line from the British throne.

In China,
the Qing
Dynasty had extensive protocols to protect Manchus from the Peking's
endemic smallpox. Most notably, the Kangxi Emperor was promoted to the throne
because he had survived the disease, ahead of older brothers who
had not yet had it.

Mozart and Beethoven contracted and survived the disease as
children; both had visible pockmark scars on their faces.

Both George Washington and
Abraham Lincoln, Presidents of the
United States, contracted and recovered from the disease. Lincoln
was diagnosed with a mild form of the disease in late November 1863
having probably contracted it from his son Tad. U.S. President
Andrew Jackson and his older brother,
Robert, contracted smallpox in his youth while imprisoned by the
British during the American Revolutionary War. While Robert died
from the disease, Andrew survived it and eventually served as the
7th President of the United States.

Crime figure Lucky Luciano contracted
the disease in 1907 at the age of ten, upon coming to New York from
Sicily.